Role of Progranulin in Mediating the Anti-Inflammatory Property of High-Density L

描述(申请人提供)：高密度脂蛋白(高密度脂蛋白)是血浆中最小、密度最大的脂蛋白。过去40年的流行病学研究一直发现，高密度脂蛋白水平与心血管疾病的发病率呈负相关。高密度脂蛋白的保护作用在很大程度上归因于其在胆固醇反向转运中的作用或其抗炎特性。基于高密度脂蛋白阻断肿瘤坏死因子-a诱导的内皮细胞中细胞黏附分子VCAM-1和ICAM-1表达的能力，该药物的抗炎特性于1995年被描述。尽管许多研究证实了这一发现，但这种抗炎特性背后的机制仍不清楚。我建议关注一种新的候选药物来调节高密度脂蛋白的抗炎特性。原颗粒蛋白是一种分泌型生长因子，在许多组织中表达，并在血液中循环。在一些家族性额颞部痴呆患者中，原颗粒基因GRN发生了突变。据报道，原颗粒蛋白与高密度脂蛋白有关。有趣的是，最近的研究表明，原颗粒与肿瘤坏死因子受体结合，从而在原颗粒和炎症之间建立了联系。具体地说，目前的模型假设，前列腺素通过与肿瘤坏死因子-a竞争结合肿瘤坏死因子受体来拮抗肿瘤坏死因子信号转导。此外，缺乏原颗粒的小鼠对胶原诱导的关节炎的易感性增加，这说明了涉及炎症的功能后果。这提出了一个耐人寻味的假设，即原颗粒显著有助于高密度脂蛋白的抗炎特性。这些研究的完成有望为了解高密度脂蛋白抗炎特性的分子基础提供重要的见解。从这些研究中收集到的知识可能会对心血管疾病的预防和治疗产生治疗意义。此外，它将与GRN基因突变的个人直接相关，GRN基因在某些额颞叶痴呆病例中发生突变。

DESCRIPTION (provided by applicant): High-density lipoprotein (HDL) is the smallest, most dense lipoprotein in plasma. Epidemiological studies from the past four decades have consistently found that HDL levels are inversely correlated with the incidence of cardiovascular disease. The protective effect of HDL is largely attributed to either its role in reverse cholesterl transport or its anti-inflammatory property. The anti-inflammatory property was described in 1995, based on HDL's ability to block TNF-a-induced expression of the cellular adhesion molecules VCAM-1 and ICAM-1 in endothelial cells. Although numerous studies have confirmed this finding, the mechanism underlying this anti-inflammatory property remains unknown. I propose to focus on a new candidate for mediating HDL's anti-inflammatory property. Progranulin is a secreted growth factor that is expressed in many tissues and circulates in the blood. The progranulin gene, GRN, is mutated in some cases of familial frontotemporal dementia. Progranulin has been reported to be associated with HDL. Interestingly, recent studies revealed that progranulin binds to TNF receptors, thereby establishing a link between progranulin and inflammation. Specifically, current models posit that progranulin antagonizes TNF signaling by competing with TNF-a for binding to TNF receptors. Further, mice lacking progranulin have enhanced susceptibility to collagen-induced arthritis, illustrating functional consequences involving inflammation. This raises the intriguing hypothesis that progranulin significantly contributes to the anti-inflammatory property of HDL. Completion of these studies is expected to provide important insights into the molecular basis underlying HDL's anti-inflammatory property. Knowledge gleaned from these studies will likely have therapeutic implications for the prevention and treatment of cardiovascular disease. Moreover, it would be directly relevant to individuals with mutations in the GRN gene, which is mutated in some cases of frontotemporal dementia.